Clinical Trials /

Osimertinib (AZD9291) in First-line Locally Advanced or Metastatic NSCLC Patients With EGFR and EGFR T790M

NCT02841579

Description:

The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. Safety and efficacy will also be measured.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Osimertinib (AZD9291) in First-line Locally Advanced or Metastatic NSCLC Patients With EGFR and EGFR T790M
  • Official Title: A Phase IIa Clinical Trial to Evaluate the Safety and Efficacy of Osimertinib (AZD9291) in First-line Patients With EGFR Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer and Concomitant EGFR T790M Mutation at Time of Diagnosis

Clinical Trial IDs

  • ORG STUDY ID: MedOPP112
  • NCT ID: NCT02841579

Conditions

  • Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
OsimertinibAZD9291Osimertinib

Purpose

The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. Safety and efficacy will also be measured.

Detailed Description

      Naïve patients ≥ 18 years of age with histological confirmation of locally advanced or
      metastatic, non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation
      and concomitant T790M mutation. Evidence of measurable or evaluable metastatic disease is
      required.

      Primary objective:

        -  To evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response
           rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M
           mutation at diagnosis as defined by RECIST 1.1 criteria.

      Secondary objectives:

        -  To determine the safety and tolerability profile of osimertinib (AZD9291), measured
           using the number and severity of AEs entered into the Case Report Form (CRF); chemistry,
           blood count, vital signs, physical examination, weight, ECG and performance status (S).

        -  To determine other efficacy parameters such as progression-free survival (PFS), overall
           survival (OS), time to treatment failure (TTF), duration of response (DOR), disease
           control rate (DCR), and tumor shrinkage (TS).

        -  To correlate the parameters of clinical response efficacy documented with the EGFR
           mutational status.

        -  To carry out a longitudinal analysis of EGFR mutations (including the T790M mutation) in
           plasma and serum.

        -  To determine levels of BIM mRNA as well as mRNA levels of other biomarkers related to
           EGFR TKI response and determine whether they are predictors of treatment response.

        -  To identify mechanisms of acquired resistance to osimertinib (AZD9291); mutations at the
           site of covalent binding to the drug (C797) or other mutations in tissue or blood.

      Type of study: Multicenter, international, single-arm, open-label, non-controlled phase IIa
      clinical study.

      Treatment: Patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os
      (p.o.) daily.
    

Trial Arms

NameTypeDescriptionInterventions
OsimertinibExperimentalThe patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os (p.o.) daily. Patients will receive study treatment until disease progression or occurrence of unacceptable side effects up to 78 weeks from the time of the first administered dose.
  • Osimertinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patient aged 18 years or older

          -  Patients with histological confirmation of locally advanced or metastatic,
             non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation and
             concomitant T790M mutation who are not candidates for local curative treatment.

          -  Patients with a M1a stage according to the TNM version 7 including M1a (malignant
             effusion) or M1b (distant metastasis), or locally advanced disease that is not a
             candidate for curative treatment (including patients who progress after
             chemoradiotherapy in stage III disease).

          -  Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon
             18 (G719X) and concomitant T790M mutation before treatment confirmed centrally.

          -  ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2.

          -  Existence of measurable or evaluable disease (as per RECIST 1.1 criteria). Patients
             with asymptomatic and stable brain metastases are eligible for the study.

          -  Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection
             of the primary tumor or metastatic tumor tissue, within the 60 days prior to study
             entry.

          -  Life expectancy ≥12 weeks.

          -  Adequate hematologic function:

               -  Absolute neutrophil count (ANC) > 1.5 x 109/L

               -  platelet count > 100.0 x109/L

               -  hemoglobin > 9.0 g/dL (> 6.2 mmol/L).

          -  Adequate coagulation: INR ≤ 1.5.

          -  Adequate liver function

          -  Adequate renal function.

          -  Capacity to swallow, patient capable of completing treatment and accessible, ensuring
             proper follow-up.

          -  Patients able to complete study and within geographical proximity allowing for
             adequate follow-up.

          -  Resolution of all acute toxic effects of previous anti-cancer therapy (which can only
             be adjuvant or neoadjuvant) or surgical interventions not exceeding grade ≤ 1
             according to the NCI CTCAE version 4.0 (except for alopecia or other side effects that
             the investigator does not consider to be a risk to patient safety).

          -  All men or women of childbearing potential must use a contraception method during the
             study treatment and for at least 12 months after the last dose of the study drug.

          -  Signed and dated informed consent form

        Exclusion Criteria:

          -  Locally advanced lung cancer candidate for curative treatment through radical surgery
             and/or radio(chemo)therapy.

          -  Patients diagnosed with another lung cancer subtype, patients with mixed NSCLC with
             predominantly squamous cell cancer, or with any small-cell lung cancer component.

          -  Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon
             18 (G719X) and concomitant T790M mutation before treatment that have not been
             confirmed centrally.

          -  Patients who have received prior antineoplastic treatment for advanced disease.

          -  Second active neoplasia

          -  Patients with just one measurable or evaluable tumor lesion that has been resected or
             irradiated prior to their enrollment in the study.

          -  Medical history of Interstitial Lung Disease (ILD) induced by drugs, radiation
             pneumonitis requiring steroid treatment or any evidence of clinically active ILD.

          -  Corrected QT Interval (QTc) >470 msec, obtained from 3 ECGs at rest, using the QTc
             value determined according to the clinical screening ECG machine.

          -  Any clinically significant abnormality in ECG rhythm, conduction or morphology at
             rest.

          -  Any factor that increases the risk of QTc prolongation or risk of irregular heartbeat
             or sudden inexplicable death under the age of 40 in first-degree relatives or any
             concomitant medications that prolong the QT interval.

          -  Uncontrolled, active or symptomatic metastases of CNS, carcinomatous meningitis or
             leptomeningeal disease indicated by known clinical symptoms, cerebral edema and/or
             progressive neoplasia. Patients with history of CNS metastasis or compression of the
             spinal cord are eligible if they have received local final treatment (e.g.,
             radiotherapy, stereotactic surgery) and if they have remained clinically stable
             without using anticonvulsants and corticosteroids for a minimum of 4 weeks prior to
             the first day of study treatment.

          -  Refractory nauseas and vomiting, chronic gastrointestinal disease, inability to
             swallow study drug or significant intestinal resection that restricts the adequate
             absorption of osimertinib (AZD9291).

          -  Patients who have had a surgical procedure unrelated to the study within 7 days prior
             to the administration of the drug or a significant traumatic lesion during the 4 weeks
             prior to starting the administration of the study drug, patients who have not
             recovered from the side effects of any major surgery or patients who might need major
             surgery during the course of the study.

          -  Pregnant or breastfeeding women. Women of childbearing potential, including women who
             had their last menstrual period within the last two years, must have a negative serum
             or urine pregnancy test in the 7 days prior to the start of the treatment.

          -  Patients who are not willing to use an adequate contraception method until 12 months
             after the last dose of study treatment.

          -  Patients with a serious concomitant systemic disorder (e.g., active infection,
             including HIV or heart disease) that is incompatible with the study (in the opinion of
             the investigator), history of bleeding diathesis or anticoagulant therapy (the use of
             low molecular weight heparin is permitted provided that it is used for prophylaxis).

          -  Patients with a history of cancer that has been completely treated, with no evidence
             of malignant disease currently cannot be enrolled in the study if their chemotherapy
             was completed less than 6 months prior and/or have received a bone marrow transplant
             less than 2 years before the first day of study treatment.

          -  Prior treatment with cytotoxic chemotherapy for advanced NSCLC; neoadjuvant/adjuvant
             chemotherapy is permitted if at least 6 months have elapsed between the end of
             chemotherapy and the first day of study treatment.

          -  Patients who have received prior EGFR treatments for lung cancer.

          -  Patients who have received treatment with an investigational drug within 3 weeks
             before the first day of study treatment.

          -  Treatment with prohibited drugs within 14 days before the first day of study
             treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:Defined as the rate of complete responses [CR] or partial responses [PR] to treatment in accordance to the guidelines of RECIST version 1.1 criteria

Secondary Outcome Measures

Measure:Grade 3 or 4 adverse events and SAEs
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:Patient safety and adverse events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the U.S. National Cancer Institute (NCI), version 4
Measure:Overall survival
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:Time from treatment start to the time of death due to any cause
Measure:Time to treatment failure
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:Time from treatment start to the time at which the patient discontinues treatment due to any cause
Measure:Duration of response
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:Time from the first documented response to documented disease progression or death
Measure:Disease control rate
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:Percentage of patients with complete response, partial response or stable disease for a minimum of 24 weeks, assessed in accordance with the modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, during all study period from baseline up to 78 weeks after patient entry
Measure:Tumor shrinkage
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:
Measure:Correlation ratio between mutational status and clinical response
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:Correlation ratio of mutational status and documented clinical response
Measure:Tumour EGFR mutation status by histology
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:
Measure:Overall plasma EGFR mutation status
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:Measured by Percentage of patients with a positive EGFR mutation in plasma
Measure:BIM mRNA levels
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:
Measure:Acquired resistance to osimertinib (AZD9291) by histology
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:Percentage of patients who develop anti-drug mutations in tumour tissue
Measure:Overall plasma acquired resistance to osimertinib (AZD9291)
Time Frame:Baseline up to 78 weeks after patient entry
Safety Issue:
Description:Percentage of patients who develop anti-drug mutations in plasma

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:MedSIR

Last Updated

January 3, 2017